1,2,4-Triazol-3-one antidepressants

ABSTRACT

Phenoxyalkyl substituted-1,2,4-triazolones having anti-depressant properties typified by 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part application of Ser. No. 351,834 filedFeb. 24, 1982 and now abandoned which is a continuation-in-part of Ser.No. 244,464 filed Mar. 16, 1981 and now U.S. Pat. No. 4,338,317.

BACKGROUND OF THE INVENTION

The present invention relates to 1,2,4-triazole heterocyclic carboncompounds and to their preparation and use. More particularly, theinvention relates to2-[3-[4-(halophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(phenoxyalkyl)-2H-1,2,4-triazol-3(4H)-onesand therapeutic use in treating depression.

U.S. Pat. No. 3,857,845 to G. Palazzo describes the compound1-[3-(4-meta-chlorophenyl-1-piperazinyl)propyl]-3,4-diethyl-Δ²-1,2,4-triazolin-5-one depicted structurally below. ##STR1##Alternatively, the compound can be named2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-4,5-diethyl-2H-1,2,4-triazol-3(4H)-one,and is commonly called etoperidone.

Regarding utility, the U.S. Pat. No. 3,857,845 Palazzo patent disclosesthat etoperidone has pharmacological properties typical of tranquilizersincluding sedation, reduced activity towards the experimentor and lowermotor activity. In addition, hypotensive and analgesic activity arereported with possible use as an antianxiety agent and tranquilizer inhuman therapy mentioned.

U.S. Pat. No. 3,381,009 to G. Palazzo, et al., discloses1,2,4-triazolo[4,3-a]pyridines of the following general formula ##STR2##wherein R is hydrogen or methyl and R' is hydrogen, alkyl (1-4C), alkoxy(1-4C), or halogen. The compounds are said to exhibit tranqualizingaction, hypotensive action, and analgesic action according to variousanimal tests. With respect to tranquilizing action, the pharmacologicalprofile includes such behavioral effects as sedation, decrease in motoractivity, hypotonia, high dose induced muscular non-coordination andataxia, and inhibition of conditioned reflexes in the rat. According tothe U.S. Pat. No. 3,381,009, data relative to behavioral, adrenolyticand anti-serotonin effects indicate that the compounds resemble majortranquilizers, such as chlorpromazine more than minor ones such asmeprobamate. Pharmacological properties of one compound in particular,2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one,have been described in more detail by Silvestrini, et al., InternationalJournal of Neuropharmacology, 7, 587-599 (1968). The aforementionedcompound, commonly known as trazodone, has been studied extensively inman and is considered to be an antidepressive equivalent ineffectiveness to imipramine but with fewer side effects (Fabre, et al.,Current Therapeutic Research, 25, 827-834 (1979)).

SUMMARY OF THE INVENTION AND DESCRIPTION OF PREFERRED EMBODIMENTS

Broadly described, the present invention is concerned withpiperazinylalkyl-1,2,4-triazol-3-ones characterized by Formula I##STR3## wherein n is the integer 2-4, R is halogen, R₁ is hydrogen,halogen or alkoxy, and pharmaceutically acceptable salts thereof. Theterm "halogen" or halo as used herein comprehends fluorine, iodine andmost preferably bromine and chlorine. The term alkoxy as used hereincomprehends from 1 to 4 carbon atoms, such as methoxy, ethoxy,tert-butoxy and the like.

Formula I comprehends compounds of U.S. patent application Ser. No.244,464, particularly those wherein R₁ is hydrogen and n is 2. Thus, thenew subject matter of the instant continuation-in-part applicationconstitutes compounds of Formula I' ##STR4## wherein R is halogen, R₁ ishalogen or alkoxy when n is 2-4, R₁ is also hydrogen when n is 3-4, andpharmaceutically acceptable salts thereof.

The pharmaceutically acceptable acid addition salts are those in whichthe anion does not contribute significantly to the toxicity orpharmacological activity of the salt and, as such, they are thepharmacological equivalents of the bases of Formula I. They aregenerally preferred for medical usage. In some instances, they havephysical properties which makes them more desirable for pharmaceuticalformulation purposes such as solubility, lack of hygroscopicity,compressibility with respect to tablet formation and compatibility withother ingredients with which the substance may be used forpharmaceutical purposes. The salts are made by reaction of the base ofFormula I with the selected acid preferably by contact in solution. Theymay also be made by metathesis or treatment with an ion exchange resinunder conditions in which the anion of one salt of the substance of theFormula I is replaced by another anion under conditions which allow forseparation of the desired species such as by precipitation from solutionor extraction into a solvent, or elution from or retention on an ionexchange resin. Pharmaceutically acceptable acids for the purposes ofsalt formation of the substances of Formula I include hydrochloric,hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric,nitric, mucic, isethionic, palmitic, heptanoic, and others.

In its most preferred embodiment, the present invention provides thecompound of Formula I wherein R is meta-chloro which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(Ia), alternatively named herein as2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.##STR5##

The Formula I compounds are useful pharmacological agents withpsychotropic properties. In this regard, they exhibit selective centralnervous system effects associated with antidepressant activity accordingto conventional in vivo test systems such as those listed below.

    ______________________________________    Behavioral Test                   Reference    ______________________________________    Suppression of conditioned                   Albert, et al., Pharmacologist, 4,    avoidance response (CAR)                   152 (1962).    Prevention of reserpine                   Niemegeers,    ptosis in mice Industrial Pharmacology,    (antidepressant)                   Vol. 2 - Antidepressants, Ed. by                   S. Fielding and H. Lal, pp. 73-98,                   Futura, New York, N.Y., (1975).    Potentiation of alcohol                     --    Hypnois in the mouse    (sedative)    ______________________________________

In these tests,2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one(Ia) suppressed CAR in the rat and prevented but did not reversereserpine ptosis in the mouse. Such activity is characteristic of mostclinically useful antidepressant agents. Sedation is a common sideeffect of antidepressants. In this regard, compound Ia exhibited onlyminimal activity in potentiating alcohol hypnosis in the mouse which isindicative of a relative lack of this adverse reaction.

As further indication of the psychotropic activity and specificity ofthe instant compounds, state of the art in vitro central nervous systemreceptor binding methodology can be employed. Certain compounds(commonly referred to as ligands) have been identified whichpreferentially bind to specific high affinity sites in brain tissuedealing with psychotropic activity or potential for side effects.Inhibition of radiolabeled ligand binding to such specific high affinitysites is considered a measure of a compound's ability to affectcorresponding central nervous system function or cause side effects invivo.

The following tests, as well as others, can be employed in developing aprofile of the psychotropic activity of the instant compounds.

    ______________________________________    Receptor    Binding Assay               Reference    ______________________________________    Dopamine   Burt, et al., Molec. Pharmacol., 12, 800               (1976); Science, 196, 326 (1977);               Creese, et al, Science, 192, 481 (1976).    Cholinergic               Yamamura, et al., Proc. Natn. Acad. Sci.               USA 71 1725 (1974).    Alpha-receptor               Crews, et al., Science 202: 322 (1978).               Rosenblatt, et al., Brain Res. 160: 186 (1979)               U'Prichard, et al., Science 199: 197 (1978).               U'Prichard, et al., Molec. Pharmacol. 13:               454 (1977).    Serotonin Type 2               Peroutka and Snyder, Molec. Pharmacol.               16: 687 (1979).    ______________________________________

According to the foregoing assays, Compound Ia inhibits serotoninbinding and was relatively inactive with respect to dopamine receptorbinding, cholinergic receptor binding, and alpha-receptor binding. Thelatter is particularly significant in that drugs with high affinity foralpha-receptors relative to serotonin type 2 receptors are likely tocause side effects such as sedation and blood pressure lowering. Thus,the instant compounds and particularly Compound Ia are consideredimproved antidepressants with minimal side effect potential.

According to the present invention, thepiperazinylalkyl-1,2,4-triazol-3-ones characterized by Formula I areobtained by the following process which comprises treating apiperazinylalkyltriazolone of Formula II ##STR6## wherein R is halogenattached in the 2, 3 or 4 position of the phenyl ring with a suitablealkali metal base such as sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate to form an alkali metal salt thereof;and then alkylating the Formula II alkali metal salt with aphenoxyalkylhalide of Formula VII wherein R₁ is as defined above, n isthe integer 2-4 and "X" comprehends halogen, preferably chlorine orbromine, or a suitable leaving group such as sulfate, phosphate,tosylate, mesylate, and the like ##STR7## It is to be understood thatFormula II depicts a tautomer of a compound with an alternate tautomericform of Formula II'. ##STR8##

Standard labortory procedures are employed in carrying out the foregoingreaction such as those described for the alkylation step of the Gabrielsynthesis--S. Gabriel, Ber. 20, 2224 (1887). In the present case, thereactants are combined in an inert reaction solvent at temperaturesranging from about 50° C. to 200° C. Acetonitrile and xylene areparticularly preferred solvents for carrying out the reaction but othersolvents which do not adversely affect the reaction or reactants can beemployed. In this regard, solvents such as benzene, toluenedimethylformamide, n-butanol, and the like are suitable. The reactionperiod varies to some extent depending on solvent and temperatureselected. For instance, at lower temperatures, long reaction periods areneeded while at higher temperatures, alkylation is completed in ashorter time. In the case of acetonitrile or xylene, optimum yields areobtained with a reaction period of 8 to 68 hours.

A preferred process for preparing Formula I products comprises reactinga piperazinylalkyltriazolone of Formula II with a phenoxyalkylhalide ofFormula VII in the presence of an alkali metal carbonate such aspotassium carbonate or sodium carbonate in acetonitrile.

The Formula II piperazinylalkyltriazolone intermediates are preferablyobtained by alkylating hydrazine with a1-(halophenyl)-4-(3-halopropyl)piperazine to provide a1-(halophenyl)-4-(3-hydrazinopropyl)piperazine of Formula III ##STR9##which is then condensed with N-ethoxycarbonylthiopropionamide ##STR10##in a reaction inert solvent at elevated temperature. Alkanols, such asethanol, are particularly preferred as solvents with the reactionconveniently carried out at reflux temperature. Other suitable solventsinclude acetone, acetonitrile, ethylacetate, dimethylformamide, etherssuch as tetrahydrofuran and the like.

Another operable procedure for preparing Formula II intermediatescomprises heating N-ethoxycarbonylthiopropionamide with hydrazine inethanol to provide the triazolone compound of Formula IV ##STR11## whichis then alkylated with a 1-(halophenyl)-4-(3-halopropyl)piperazinecompound in xylene at reflux temperature. Compared to the previouslydescribed preparation of Formula II intermediates, this method is not assatisfactory in that the triazolone (IV) is alkylated indiscriminatelyat "two and four" positions resulting in lower yields of the desiredpiperazinylalkyltriazolone (II). For example, reaction of triazolone(IV) with 1-(3-phenyl)-4-(3-chloropropyl)piperazine in refluxing xyleneaffords the following compounds (isolated as hydrochloride salts) assecondary products in addition to the desired Formula (II)piperazinylalkyltriazolone intermediate wherein R is meta-chloro.

    ______________________________________    Secondary Products    ______________________________________     ##STR12##     ##STR13##      4-[3-[4-(3-Chlorophenyl)-1-piperazinyl]- propyl]-5-ethyl-2,4-dihydro-3H1      ,2,4- triazol-3-one hydrochloride; m.p. 210-212° C. (dec.)     ##STR14##      2,4-bis-[3-[4-(3-Chlorophenyl)- 1-piperazinyl]-propyl]-5-ethyl-      2H1,2,4-triazol-3(4H)-one hydrochloride m.p. 206-208° C.    ______________________________________      (dec.)

An alternate process for preparing a compound of Formula I comprisescondensing a Formula III 1-(halophenyl)-4-(3-hydrazinopropyl)piperazinewith a N-phenoxyethyl-N-ethoxycarbonylthiopropionamide of Formula (V)wherein R₁ is as defined above and n is 2-4. ##STR15## The condensationis carried out in a suitable reaction inert solvent such as ethanol aspreviously described for the preparation of the Formula (II)piperazinylalkyltriazolones. The Formula V intermediate can be obtainedby standard methods such as condensing methyl dithiopropionate with aN-(phenoxyalkyl)ethylcarbonate under basic conditions or alkylatingN-ethoxycarbonylthiopropionamide with a phenoxyalkylhalide of FormulaVII in the presence of an alkali metal base.

The procedures hereinabove described for preparing Formula I compoundsconstitutes a unitary process which comprises condensing an amide of theFormula VI ##STR16## wherein R' is hydrogen or R₁ -phenoxyalkyl of 2 to4 carbon atoms with a 1-(halophenyl)-4-(3-hydrazinopropyl)piperazine ofFormula III ##STR17## wherein R is halogen in a reaction inert solventat elevated temperatures to provide compounds of Formula I when R' is R₁-phenoxyalkyl and compounds of Formula II when R' is hydrogen andthereafter alkylating a Formula II compound with a phenoxyalkyl halideof Formula VII in the presence of an alkali metal base.

A still further preferred process for preparing a compound of Formula Icomprises alkylating a Formula VIII phenoxyalkyltriazolone ##STR18##wherein R₁ is hydrogen, halogen or alkoxy, and n is the integer 2-4 witha 1-(halophenyl)-4-(3-halopropyl)piperazine of Formula IX ##STR19##wherein R is halogen and X comprehends halogen, preferably chlorine orbromine, or a suitable leaving group such as sulfate, phosphate,tosylate, mesylate, and the like, in the presence of a suitable alkalimetal base such as sodium carbonate, potassium carbonate, potassiumhydroxide and preferably sodium hydroxide in a reaction inert solvent.The term "reaction inert solvent" refers to any protic or aproticsolvent or diluent which does not enter into the reaction to anysubstantial degree. Laboratory procedures and solvents previouslydisclosed as operable for the alkylation of Formula II intermediateswith Formula VII phenoxyalkyl halides are employed. In the instant case,alkanols, particularly isopropanol, are preferred.

The aforementioned preferred processes for preparing compounds ofFormula I from triazolone intermediates of Formula II and VIII can beviewed as embodiments of a unitary process which comprises alkylating acompound of Formula X ##STR20## wherein A is hydrogen or a1-(halophenyl)-4-(3-halopropyl)piperazine radical ##STR21## B ishydrogen or the phenoxyalkyl radical ##STR22## in which "R₁ " is asdefined above, "n" is the integer 2 to 4 and one of "A" or "B" must behydrogen with an alkylating agent of Formula VII or IX.

Another aspect of the instant invention provides a method for treating amammal afflicted with depression which comprises administeringsystemically to said mammal a therapeutically effective antidepressantamount of a compound of Formula I or Formula XI or a pharmaceuticallyacceptable acid addition salt thereof. An effective dose ranges from0.01 to 40 mg/kg of body weight with the dosage dependent on effectssought, manner of administration, and to some extent with the particularcompound selected. Systemic administration refers to oral, rectal andparenteral (i.e. intramuscular, intravenous and subcutaneous).Generally, it will be found that when a compound of the presentinvention is administered orally, a larger quantity of the active agentis required to produce the same effect as a smaller quantity givenparenterally. In accordance with good clinical practice, it is preferredto administer the instant compounds at a concentration level that willproduce effective antidepressant effects without causing any harmful oruntoward side effects.

The compounds of the present invention may be administered forantidepressant purposes either as individual therapeutic agents or asmixtures with other therapeutic agents. Therapeutically, they aregenerally given as pharmaceutical compositions comprised of anantidepressant amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.Pharmaceutical compositions which provide from about 1 to 500 mg. of theactive ingredient per unit dose are preferred and are conventionallyprepared as tablets, lozenges, capsules, powders, aqueous or oilysuspensions, syrups, elixirs and aqueous solutions.

The nature of the pharmaceutical composition employed will, of course,depend on the desired route of administration. For example, oralcompositions may be in the form of tablets or capsules and may containconventional excipients such as binding agents (e.g. syrup, acacia,gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g.lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine),lubricants (e.g. magnesium stearate, talc, polyethyleneglycol orsilica), disintegrants (e.g. starch) and wetting agents (e.g. sodiumlauryl sulfate). Solutions or suspensions of a Formula I compound withconventional pharmaceutical vehicles are employed for parenteralcompositions such as an aqueous solution for intravenous injection or anoily suspension for intramuscular injection.

The following non-limiting examples illustrate the process and productsof this invention. Nuclear magnetic responance (NMR) spectralcharacteristics refer to chemical shifts down field (δ) expressed asparts per million (ppm) versus tetramethylsilane as reference standard.The relative area reported for the various shifts corresponds to thenumber of hydrogen atoms in the individual substituent and the nature ofthe shifts as to multiplicity is reported as broad singlet (bs),multiplet (m), triplet (t), or qudruplet (q) with coupling constantreported where appropriate. The format is NMR (solvent): δ(relativearea, multiplicity, J value). Abbreviations employed are DMSO-d₆(deuterodimethylsulfoxide), IR (infrared), and KBr (potassium bromide).

EXAMPLE 12-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one*(IIa)

(a) 1-(3-Chloropropyl)-4-(3-chlorphenyl)piperazine Hydrochloride A 50%sodium hydroxide solution (430.6 g., 5.333 mole) is added dropwise to astirred solution of 1-(3-chlorophenyl)piperazine hydrochloride (502.0g., 2.153 mole) and 1-bromo-3-chloropropane (339.0 g., 2.153 mole) in435 ml. water and 535 ml. acetone while maintaining temperature of0°-10° C. Stirring is continued for a 16 hr. period at room temperatureand the upper organic phase then separated and concentrated underreduced pressure. The remaining residual oil is taken up in 500 ml.acetone, filtered and the filtrate concentrated under reduced pressureto an oily residue which is dissolved in boiling dilute hydrochloricacid (1.67 liter water plus 280 ml. concentrated HCl, 3.36 mole). Theoil which initially separates from the cooled acid solution, solidifieson standing and is collected, rinsed with cold water and air dried.Crystallization of this material from water employing activated charcoalaffords 438.4 g. (66%) of1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride, m.p.196.5°-198.5° C.

(b) 1-(3-Chlorophenyl)-4-(3-hydrazinopropyl)piperazine Hydrazine hydrate(10.7 g., 0.184 mole) in 20 ml. of ethanol is added slowly to1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (9.29 g.,0.03 mole) in 20 ml. of ethanol. After refluxing the mixture for a 3 hr.period, the solvent is removed under reduced pressure and 20 ml. ofwater added to the residue. A 50 ml. portion of tetrahydrofuran is addedto the aqueous mixture which is then saturated with potassium hydroxidepellets employing ice bath cooling. The tetrahydrofuran phase isseparated, dried over magnesium sulfate and concentrated under reducedpressure to afford 7.4 g. (92%) of1-(3-chlorophenyl)-4-(3-hydrazinopropyl)piperazine employed withoutfurther purification in the following step.

(c)2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one.A solution of 1-(3-chlorophenyl)-4-(3-hydrazinopropyl)piperazine (19.6g., 0.073 mole) in 90 ml. of ethanol is added toN-ethoxycarbonylthiopropionamide (12.13 g., 0.073 mole) in 30 ml. ofethanol. The mixture is refluxed for a 16 hr. period with evolution ofhydrogen sulfide and then concentrated under reduced pressure.Crystallization of residual material from ethanol affords 18.3 g. (72%)of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one,m.p. 79°-81° C.

Addition of ethanolic hydrogen chloride to a sample of the base inethanol with precipitation of the salt with ether affords2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-onehydrochloride, m.p. 165°-167° C.

Anal. Calcd. for C₁₇ H₂₄ ClN₅ O.HCl: C, 52.86; H, 6.53; N, 18.13. Found:C, 52.72; H, 6.44; N, 17.96.

NMR (DMSO-d₆): 1,15 (3H,t, 7.3 Hz), 2.16 (2H,m), 2.43 (2H,q, 7.3 Hz),3.18 (8H,m), 3.68 (4H,m), 6.89 (3H,m), 7.24 (1H,m), 11.49 (1H,bs).

IR (0.5% KBr, cm⁻¹): 770, 940, 1255, 1440, 1485, 1595, 1690, 2570, 2980.

EXAMPLE 22-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one(Ia)*

(a) Reaction in Xylene. Sodium hydroxide (2.08 g., 0.052 mole) in 10 ml.of water is added slowly to2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one(18.2 g., 0.052 mole) in 150 ml. of warm ethanol with stirring. Whenmixing is complete, distillables are removed under reduced pressure.Ethanol is added to residual material and removed under reduced pressureand the process repeated until the sodium salt of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-oneis obtained as a hard solid.

The sodium salt is pulverized, suspended in 200 ml. of xylene and mixedwith phenoxyethyl bromide (10.4 g., 0.052 mole) in 20 ml. of xylene. Theresulting mixture is refluxed with stirring for a 64 hr. period and thehot reaction mixture filtered. The filtrate is concentrated underreduced pressure and residual material taken up in ether. Insolubles arecollected and the ether filtrate concentrated to afford 22.9 g. (94%) of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-oneas the free base. Purification of the product is carried out byacidifying a solution of the free base in ethanol with ethanolichydrogen chloride, and crystallization to afford hydrated (0.25 mole)2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-onehydrochloride, m.p. 175°-177° C. (30.7% yield).

Anal. Calcd. for C₂₅ H₃₂ ClN₅ O₂.HCl.1/4H₂ O: C, 58.77; H, 6.61; N,13.71. Found: C, 58.61; H, 6.48; N, 13.68.

NMR (DMSO-d₆): 1.20 (3H,t, 7.5 Hz), 2.16 (2H,m), 2.66 (2H,q, 7.5 Hz),3.27 (8H,m), 3.74 (4H,m), 3.96 (2H,t), 4.17 (2H,t), 6.96 (6H,m), 7.29(3H,m), 11.50 (1H,bs).

IR (0.5% KBr, cm⁻¹): 755, 940, 1235, 1440, 1490, 1595, 1710, 2580, 2940.

A sample of non-hydrated2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-onehydrochloride obtained according to the above process melted at175°-177° C.

Anal. Calcd. for C₂₅ H₃₂ ClN₅ O₂.HCl: C, 59.29; H, 6.57; N, 13.83.Found: C, 59.98; H, 6.44; N, 13.58.

NMR (DMSO-d₆): 1.20 (3H,t, 7.5 Hz), 2.14 (2H,m), 2.65 (2H,q, 7.5 Hz),3.25 (8H,m), 3.72 (4H,m), 3.95 (2H,t), 4.16 (2H,t), 6.91 (6H,m), 7.25(3H,m), 11.61 (1H,bs).

C¹³ NMR (DMSO-d₆): 9.65, 18.40, 22.90, 40.57, 41.89, 44.73, 50.31,52.92, 64.95, 114.06, 114.30, 115.21, 119.12, 120.93, 129.53, 130.55,133.94, 147.92, 150.78, 153.15, 157.87.

Ir (0.5% KBr, cm⁻¹): 750, 940, 1235, 1440, 1485, 1595, 1710, 2570, 2930.

(b) Reaction in Acetonitrile With Potassium Carbonate. A mixture of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one(15 g., 0.043 mole), phenoxyethyl bromide (8.62 g., 0.043 mole),potassium carbonate (11.9 g., 0.086 mole) and a trace of potassiumiodide in 100 ml. of acetonitrile is refluxed for a 64 hr. period. Thereaction mixture is filtered, the filtrate concentrated under reducedpressure and residual material taken up in ether and filtered.Concentration of the ethereal filtrate affords 18.35 g. (91%) of thefree base product2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4h)-one.The free base is converted to the hydrochloride in ethanol employingethanolic hydrogenchloride and crystallized from ethanol to afford a 53%yield of analytically pure2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl-2H-1,2,4-triazol-3(4H)-one hydrochloride, m.p. 175°-177°C.

Anal. Calcd. for C₂₅ H₃₂ ClN₅ O₂.HCl: C, 59.29; H, 6.57; N, 13.83.Found: C, 59.42; H, 6.68; N, 13.52.

NMR (DMSO-d₆): 1.20 (3H,t, 7.5 Hz), 2.15 (2H,m), 2.65 (2H,q, 7.5 Hz),3.25 (8H,m), 3.72 (4H,m), 3.95 (2H,t), 4.16 (2H,t), 6.93 (6H,m), 7.27(3H,m), 11.61 (1H,bs).

IR (0.5% KBr, cm⁻¹): 755, 940, 1240, 1440, 1490, 1595, 1710, 2580, 2940.

EXAMPLE 32-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(3-phenoxypropyl)-3H-1,2,4-triazol-3-one(Ib) ##STR25##

A mixture of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one(3.86 g., 0.01 mole), 3-phenoxypropyl bromide (2.15 g., 0.01 mole),potassium carbonate (4.15 g., 0.01 mole) and a trace of potassium iodidein 50 ml. of acetonitrile is refluxed for a 65 hr. period. The reactionmixture is filtered, the filtrate concentrated under reduced pressureand residual material taken up in ether and filtered. Solvent is removedand further purification carried out by sequentially converting the freebase to the hydrochloride salt and then to the free base which ischromatographically treated employing a silica column withmethanol/chloroform eluant. Free base, obtained from the chromatographicseparation, is converted to the hydrochloride salt in ethanol employingethanolic hydrogen chloride to afford 1.17 g., (22% yield) ofanalytically pure2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(3-phenoxypropyl)-3H-1,2,4-triazol-3-onehydrochloride, m.p. 145°-147° C.

Anal. Calcd. for C₂₆ H₃₄ ClN₅ O₂.HCl: C, 60.00; H, 6.78; N, 13.46.Found: 60.27; H, 6.82; N, 13.67.

NMR (DMSO-d₆): 1.15 (3H,t, 7.2 Hz); 2.10 (4H,m); 2.55 (2H,q, 7.2 Hz);3.18 (6H,m); 3.75 (8H,m); 3.99 (2H,t, 6.0 Hz); 6.94 (6H,m); 7.27 (3H,m);11.70 (1H,bs).

EXAMPLE 42-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(4-phenoxybutyl)-3H-1,2,4-triazol-3-one(Ic) ##STR26##

A mixture of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3-(2H)-one(3.86 g., 0.01 mole), 4-phenoxybutyl bromide (2.29 g., 0.01 mole),potassium carbonate (4.15 g., 0.01 mole) and a trace of potassium iodidein 50 ml. of acetonitrile is refluxed for a 65 hr. period. The reactionmixture is filtered, the filtrate concentrated under reduced pressureand residual material taken up in ether and filtered. Concentration ofethereal filtrate affords the free base. Conversion of the free base tothe hydrochloride salt in ethanol with ethanolic hydrogen chloride andcrystallization of the salt from ethanol affords analytically pure2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(4-phenoxybutyl)-3H-1,2,4-triazol-3-onehydrochloride, m.p. 152°-154° C.

Anal. Calcd. for C₂₇ H₃₆ ClN₅ O₂.HCl: C, 60.68; H, 6.98; N, 13.11.Found: C, 60.70; H, 6.86; N, 13.25.

NMR (DMSO-d₆): 1.19 (3H, t, 7.4 Hz); 1.74 (4H,m); 2.19 (2H,m); 2.58(2H,q, 7.4 Hz); 3.19 (6H,m); 3.70 (6H,m); 3.99 (4H,m); 6.92 (6H,m); 7.26(3H,m); 11.70 (1H,bs).

EXAMPLE 5 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one (VIIIa,n=2) ##STR27##

(a) 3-Phenoxypropionyl Hydrazide Hydrochloride. Ethyl3-phenoxypropionate (1481.0 g., 7.62 mole) obtained according to R.Hall, et al., J. Chem. Soc., 2035 (1949) is stirred in an ice bathduring addition of 95% hydrazine (308.3 g., 9.14 mole). A precipitateforms and the mixture is allowed to stand at room temperature for 5 hr.,then refrigerated for a 16 hr. period and filtered to provide 1128.0 g.,of white solid (82.1% yield) of 3-phenoxypropionyl hydrazide.Preparation of the hydrochloride salt is carried out by dissolving3-phenoxypropionyl hydrazide (2000.6 g., 11.1 mole) in 5 liters ofmethylene chloride. The solution is stirred and chilled in an ice bathas anhydrous hydrogen chloride is bubbled into the mixture to pH 3.Solid is collected, rinsed with methylene chloride and air dried to give2100.0 g., (87.1% yield) of 3-phenoxypropionyl hydrazide hydrochloride,m.p. 145°-156° C.

(b) 1-Propionyl-4-(2-phenoxyethyl)semicarbazide. A mixture of3-phenoxypropionyl hydrazide hydrochloride (938.9 g., 4.333 mole), 6.8kg. ice-water and 3.4 liters toluene is stirred in an ice bath as asolution of sodium nitrate (328.6 g., 4.763 mole) in 1.4 liters of wateris added over a 10 min. period. The mixture is stirred for 0.5 hrs. at2° C., Celite added and the mixture filtered through a Celite bed. Thefiltrate layers are separated, and the aqueous layer extracted with two400 ml. portions of toluene. Combined toluene extracts are dried overmagnesium sulfate, filtered and the toluene solution of3-phenoxypropionyl azide added over a 1.5 hr. period to a flask heatedon a steam-bath under a nitrogen atmosphere with stirring. Followingaddition, decomposition of the azide to the phenoxyethyl isocyanateintermediate is completed by heating and stirring until gas evolutionstops. The clear, yellow solution is cooled to 20° C. and propionylhydrazide (381.8 g., 4.333 mole) obtained according to T. Rabini, etal., J. Org. Chem., 30, 2486 (1965) is added in one portion withstirring. stirring is continued and the reaction mixture chilled to 10°C. and filtered affords 792.2 g., (72.8% yield) of1-propionyl-4-(2-phenoxyethyl)semicarbazide, m.p. 178°-183° C.

(c) 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one.

A solution of potassium hydroxide (88.4 g., 1.576 mole) in 10 liters ofwater is stirred and heated to 95° C.; then1-propionyl-4-(2-phenoxyethyl)-semicarbazide (396.1 g., 1.576 mole)added and the mixture stirred at 95°-96° C. for a 40 min. period.Insolubles are collected and the filtrate stirred in an ice bath as 145ml. (1.74 mole) of 37% hydrochloric acid is added. Stirring is continuedwith cooling to provide a white solid which is collected, rinsed withwater and air dried to provide 233.5 g., (63.5% yield) of5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one, m.p. 136°-139° C.

Anal. Calcd. for C₁₂ H₁₅ N₃ O₂ : C, 61.79; H, 6.48; N, 18.01. Found: C,61.77; H, 6.50; N, 17.91.

EXAMPLE 62-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(Ia) ##STR28##

Reaction in Isopropanol with Sodium Hydroxide. A mixture of5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one (60.0 g., 0.257mole), 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride(79.7 g., 0.257 mole), sodium hydroxide (26.7 g., 0.669 mole) and 400ml. of isopropanol is stirred and heated at reflux for a period of 10 to18 hrs. The mixture is acidified with 35 ml. (0.42 mole) of 37%hydrochloric acid and the solvent concentrated under reduced pressure.Residual material is stirred with 400 ml. of methylene chloride,filtered, and the filtrate concentrated under reduced pressure.Crystallization of the residue from 600 ml. of isopropanol affords 81.5g. (62.5% yield) of product which is further crystallized from water andthen isopropanol to provide2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-onehydrochloride, m.p. 180°- 182.5° C.

Spectral (NMR, ¹³ C NMR, IR) and elemental analysis data are consistentand in accord with that obtained for the identical product of Example 2.

EXAMPLE 7 Additional Formula I Products

By substituting the enumerated phenoxyalkyl halide for phenoxyethylbromide in Example 2, alkylation of2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-oneis carried out to provide the indicated Formula I compounds.

    ______________________________________     ##STR29##      Compound    R.sub.1    n       Phenoxyalkyl halide    ______________________________________    (Id) 4-Cl  2       4-chlorophenoxyethyl chloride    (Ie) 3-Cl  2       3-chlorophenoxyethyl chloride    (If) 4-F   2       4-fluorophenoxyethyl bromide    (Ig) 4-F   3       4-fluorophenoxypropyl chloride    (Ih) 3-CH.sub.3 O               2       3-methoxyphenoxyethyl chloride    (Ii) 4-CH.sub.3 O               2       4-methoxyphenoxyethyl chloride    ______________________________________

FURTHER DETAILED DESCRIPTION OF THE INVENTION

A number of additional compounds similar to those defined by Formula (I)above have antidepressant properties. For instance, they inhibitserotonin type 2 binding at concentrations less than 1000 nanomolar, acharacteristic of clinically useful antidepressants. Formula (XI) belowredefines the scope of the invention to include all of these additionalsubstances illustrated in Examples 8 and 9 and the subject matter ofFormula (I'). Formula (XI) excludes the claimed subject matter ofapplicants' first filed U.S. patent application Ser. No. 244,464 whichissued as U.S. Pat. No. 4,338,317 July 6, 1982. Thus the presentinvention comprehends a compound of Formula XI ##STR30## wherein n is2-4; R₂ is hydrogen or lower alkyl of 1 to 4 carbon; X₁ is oxygen or adirect bond; Y is hydrogen, halogen, lower alkoxy of 1 to 4 carbon orCF₃ with the proviso that when Y is hydrogen, n cannot be 2, R₂ cannotbe ethyl, X₁ cannot be oxygen and Z cannot be phenyl having a monohalogen substituent; Z is benzyl or a radical selected from the group##STR31## wherein R₃ is hydrogen or halogen; R₄ is halogen or CF₃ ; R₅is hydrogen, halogen or cyano; R₆ is hydrogen or halogen; or apharmaceutically acceptable acid addition salt thereof.

The compounds of Formula (XI) are obtained according to methodspreviously set forth or by modifications illustrated in the followingscheme 1 and 2 flow diagrams. ##STR32##

The process of Scheme 1 for preparing a compound of Formula (XI)comprises alkylating a Formula (XII) triazolone with apiperazinylpropyl-X' of Formula (XIII) wherein X' comprehends halogen(preferably chlorine or bromine) or a suitable leaving group such assulfate, phosphate, tosylate, mesylate, and the like, in the presence ofa suitable alkali metal base such as sodium carbonate, potassiumcarbonate, potassium hydroxide, sodium hydroxide or tetrabutylammoniumhydrogen sulfate in a reaction inert solvent. A trace of potassiumiodide is generally used as a catalyst. Laboratory procedures andsolvents previously disclosed for the alkylation of Formula IIintermediates with Formula VII phenoxyalkylhalides are operable inaddition to alkanols, particularly isopropanol. ##STR33##

The process of Scheme 2 for preparing a compound of Formula (XI)comprises reacting p-toluenesulfonyl chloride (tosyl chloride) with aFormula (XIV) alcohol to provide the tolsylate of Formula (XV) andfurther reacting the tosylate (XV) with a substituted piperazine (XVI).In converting the tosylate to the triazolone product (XI) the Formula(XVI) substituted piperazine is reacted with the tosylate (XV) bydissolving the tosylate and piperazine nucleophile (1.1 mol eq) in areaction inert solvent such as methylene chloride employing an acidscavenger such as the organic base N,N-diisopropylethylamine.

In the foregoing formulas of Schemes 1 and 2, "Y, X₁, n, R₂ and Z" areas previously defined for Formula XI).

The compounds of Formula (XI) are obtained according to methodspreviously set forth or by modifications illustrated below which areembodied in a unitary process comprising reacting a compound of FormulaX' ##STR34## wherein A' is hydrogen or a piperazinyl radical (a)##STR35## or a radical (b) ##STR36## wherein X" is a leaving group suchas halogen, sulfate, phosphate, mesylate and preferably tosylate; and

B' is hydrogen or a radical (c) ##STR37## with an alkylating agent ofFormula VII or XIII or a piperazine of Formula XVI when A' is radical(b) and B' is radical (c).

EXAMPLE 8 Preparation of Formula XI Compounds by Alkylating a Formula(XII) Triazolone

Equimolar amounts of the requisite triazolone (XII) andpiperazinylpropyl chloride (XIII, X'=Cl), anhydrous pulverized potassiumcarbonate (3-4 mol eq), tetrabutylammonium hydrogen sulfate (0.1 mol eq)and potassium iodide (0.05 mol eq) are heated at reflux in acetonitrilefor a 24-48 hr. period with vigorous stirring while maintaininganhydrous conditions or under a nitrogen atmosphere. Conventionalmethods such as thin layer chromatography are employed to determine whenthe reaction is complete. Excess acetonitrile is removed under reducedpressure and the resulting mixture partitioned between water andmethylene chloride. The organic extract is dried with sodium carbonateor magnesium sulfate, filtered and concentrated in vacuo to afford thecrude product usually as a viscous oil. Purification of the product iscarried out by conventional flash chromatography (W. C. Still, et al.,J. Org. Chem., 43, 2923 (1978)) with subsequent conversion to apharmaceutically acceptable salt such as the hydrochloride.

Adaptation of this procedure to1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (XIII, X'=Cl,Z=3-chlorophenyl) with the requisite triazolone (XII) provides theFormula XI products indicated.

(a)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-[2-(2-METHOXYPHENOXY)ETHYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE HYDRATE (XI, Y=2--CH₃ O, X₁ =0, n=2, R₂ =C₂ H₅,Z=3-chlorophenyl). Crystallized from ethyl acetate, m.p. 125°-128° C.

Anal. Calcd. for C₂₆ H₃₄ ClN₅ O₃.HCl.0.4H₂ O: C, 57.44; H, 6.64; N,12.88. Found: C, 57.28; H, 6.54; N, 13.15.

NMR (DMSO-d₆): 1.20 (3,t, 7.4 H₃); 2.15 (2,m); 2.76 (2,q, 7.4 H_(z));3.20 (8,m); 3.71 (3,s); 3.90 (8,m); 6.89 (7,m); 7.24 (1,m); 11.55(1,bs).

(b)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-(1,1-DIMETHYLETHYL)-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =tert-butyl, Z=3-chlorophenyl).Crystallized from ethanol-ether, m.p. 156°-159° C.

Anal. Calcd. for C₂₇ H₃₆ ClN₅ O₂.HCl: C, 60.67; H, 6.98; N, 13.10.Found: C, 60.85; H, 6.93; N, 12.79.

NMR (DMSO-d₆): 1.36 (9,s); 2.18 (2,m); 3.20 (8,m); 3.72 (4,m); 4.21(4,m); 6.96 (6,m); 7.24 (3,m); 11.75 (1,bs).

(c)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-[2-(4-METHOXYPHENOXY)ETHYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE HEMIHYDRATE (XI, Y=4--CH₃ O, X₁ =0, n=2, R₂ =C₂ H₅,Z=3-chlorophenyl). Crystallized from ethanol, m.p. 112°-117° C.

Anal. Calcd. for C₂₆ H₃₄ ClN₅ O₃.HCl.0.5H₂ O: C, 57.25; H, 6.65; N,12.84; H₂ O, 1.65. Found: C, 57.51; H, 6.57; N, 12.54; H₂ O, 1.68.

NMR (DMSO-d₆): 1.20 (3,t, 7.2 Hz); 2.16 (2,m); 2.65 (2,q, 7.2 Hz); 3.16(8,m); 3.67 (3,s); 3.90 (8,m); 6.83 (4,s); 6.95 (3,m);

(d)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-[2-[3-(TRIFLUOROMETHYL)PHENOXY]ETHYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE HEMIHYDRATE (XI, Y=3--CF₃, X₁ =0, n=2, R₂ =C₂ H₅,Z=3-chlorophenyl). Crystallized from ethanol-ether, m.p. 142°-144° C.

Anal. Calcd. for C₂₆ H₃₁ ClF₃ N₅ O₂.HCl.0.5H₂ O: C, 53.52; H, 5.70; N,12.00; H₂ O, 1.54. Found: C, 53,35; H, 5.58; N, 11.75; H₂ O, 1.88.

NMR (DMSO-d₆): 1.20 (3,t, 7.2 Hz); 2.17 (2,m); 2.66 (2,q, 7.2 Hz); 3.28(8,m); 3.72 (9,m); 3.96 (2,t, 5.0 Hz); 4.26 (2,t, 5.0 Hz); 6.89 (3,m);7.28 (4,m); 7.50 (1,m); 11.60 (1,bs).

(e)4-[3-(3-CHLOROPHENOXY)PROPYL]-2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-3H-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=3-Cl, X₁ =0, n=3, R₂ =C₂ H₅, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 134°-137° C.

Anal. Calcd. for C₂₆ H₃₃ Cl₂ N₅ O₂.HCl: C, 56.27; H, 6.18; N, 12.62.Found: C, 56.54; H, 6.27; N, 12.67.

NMR (DMSO-d₆): 1.16 (3,t, 7.4 Hz); 2.10 (4,m); 2.55 (2,q, 7.4 Hz); 3.20(8,m); 3.74 (6,m); 4.02 (2,m); 6.95 (6,m); 7.24 (3,m); 11.76 (1,bs).

(f)4-[2-(3-CHLOROPHENOXY)ETHYL]-2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=3-Cl, X₁ =0, n=2, R₂ =C₂ H₅, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 181°-183° C.

Anal. Calcd. for C₂₅ H₃₁ Cl₂ N₅ O₂.HCl: C, 55.51; H, 5.96; N, 12.95.Found: C, 55.73; H, 6.16; N, 12.67.

NMR (DMSO-d₆): 1.20 (3,t, 7.2 Hz); 2.18 (2,m); 2.65 (2,q, 7.2 Hz); 3.18(6,m); 3.72 (6,m); 3.95 (2,t, 5.0 Hz); 4.20 (2,t, 5.0 Hz); 6.98 (6,m);7.24 (2,m); 11.60 (1,bs).

(g)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-[3-[3-(TRIFLUOROMETHYL)PHENOXY]PROPYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=3-CF₃, X₁ =0, n=3, R₂ =C₂ H₅, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 153°-154° C.

Anal. Calcd. for C₂₇ H₃₃ ClF₃ N₅ O₂.HCl: C, 55.11; H, 5.82; N, 11.90.Found: C, 55.15; H, 5.78; N, 11.95.

NMR (DMSO-d₆): 1.17 (3,t, 7.2 Hz); 2.11 (4,m); 2.56 (2,q, 7.2 Hz); 3.20(8,m); 3.78 (6,m); 4.10 (2,t, 6.0 Hz); 6.95 (3,m); 7.20 (4,m); 7.55(1,m); 11.75 (1,bs).

(h)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(3-PHENYLPROPYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =direct bond, n=3, R₂ =C₂ H₅,Z=3-chlorophenyl). Crystallized from ethanol, m.p. 176°-177° C.

Anal. Calcd. for C₂₆ H₃₄ ClN₅ O.HCl: C, 61.90; H, 6.99; N, 13.88. Found:C, 61.96; H, 7.01; N, 13.99.

NMR (DMSO-d₆): 1.18 (3,t, 7.5 Hz); 2.00 (4,m); 2.60 (4,m); 3.20 (6,m);3.68 (8,m); 6.92 (3,m); 7.24 (6,m); 11.68 (1,bs).

(i)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(4-PHENYLBUTYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =direct bond, n=4, R₂ =C₂ H₅,Z=3-chlorophenyl). Crystallized from ethanol, m.p. 190°-192° C.

Anal. Calcd. for C₂₇ H₃₆ ClN₅ O.HCl: C, 62.55; H, 7.20; N, 13.51. Found:C, 62.41; H, 7.24; N, 13.56.

NMR (DMSO-d₆): 1.16 (3,t, 7.2 Hz); 1.59 (4,m); 2.15 (2,m); 2.58 (4,m);3.18 (4,m); 3.60 (10,m); 6.91 (3,m); 7.20 (6,m); 11.70 (1,bs).

(j)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =H, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 140°-142° C.

Anal. Calcd. for C₂₃ H₂₈ ClN₅ O₂.HCl: C, 57.74; H, 6.11; N, 14.64.Found: C, 57.71; H, 6.10; N, 14.44.

NMR (DMSO-d₆): 2.18 (2,m); 3.16 (6,m); 3.49 (2,m); 3.78 (4,m); 3.97(2,t, 5.0 Hz); 4.20 (2,t, 5.0 Hz); 6.99 (6,m); 7.23 (3,m); 8.06 (1,s);11.65 (1,bs).

(k)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-2,4-DIHYDRO-4-[2-(3-CHLOROPHENOXY)ETHYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=3-Cl, X₁ =0, n=2, R₂ =H, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 158°-160° C.

Anal. Calcd. for C₂₃ H₂₇ Cl₂ N₅ O₂.HCl: C, 53.86; H, 5.50; N, 13.66.Found: C, 54.14; H, 5.40; N, 13.68.

NMR (DMSO-d₆): 2.20 (2,m); 3.19 (8,m); 3.69 (4,m); 3.48 (2,m); 4.25(2,t, 5.0 Hz); 7.02 (8,m); 8.07 (1,s); 11.65 (1,bs).

(l)4-[3-(3-CHLOROPHENOXY)PROPYL]-2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE HYDRATE (XI, Y=3-Cl, X₁ =0, n=3, R₂ =H, Z=3-chlorophenyl).Crystallized from ethanol, m.p. 140°-144° C.

Anal. Calcd. for C₂₄ H₂₉ Cl₂ N₅ O₂.1.4HCl.0.25H₂ O: C, 52.80; H, 5.71;N, 12.83; H₂ O, 0.82. Found: C, 52.95; H, 5.63; N, 12.80; H₂ O, 0.84.

NMR (DMSO-d₆): 2.12 (4,m); 3.18 (8,m); 3.75 (6,m); 4.02 (2,t, 6.0 Hz);6.48 (6,m); 7.24 (2,m); 7.65 (1,bs); 8.04 (1,s); 11.60 (1,bs).

(m)2-[3-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]PROPYL]-2,4-DIHYDRO-4-[3-[3-(TRIFLUOROMETHYL)PHENOXY]PROPYL]-3H-1,2,4-TRIAZOL-3-ONEDIHYDROCHLORIDE HYDRATE (XI, Y=3-CF₃, X₁ =0, n=3, R₂ =H,Z=3-chlorophenyl). Crystallized from ethanol, m.p. 153°-157° C.

Anal. Calcd. for C₂₅ H₂₉ ClF₃ N₅ O₂.2HCl.0.4H₂ O: C, 49.71; H, 5.31; N,11.59; H₂ O, 1.19. Found: C, 49.83; N, 5.28; N, 11.45; H₂ O, 1.14.

NMR (DMSO-d₆): 2.14 (4,m); 3.19 (8,m); 3.78 (6,m); 4.10 (2,t, 6.0 Hz);6.92 (3,m); 7.21 (4,m); 7.52 (1,m); 8.07 (1,s); 9.24 (1.5,bs); 11.65(1,bs).

EXAMPLE 9 Preparation of Formula XI Compounds by Alkylating a FormulaXVI Piperazine

A methylene chloride solution of the requisite triazolone tosylate (XV),1.1 mol eq of the substituted piperazine (XVI) andN,N-diisopropylethylamine (1.0 mol eq) is maintained at 40°-45° C. for a24-72 hr. period. The Formula (XI) triazolone product is purified byflash chromatography as free base. Conversion to pharmaceuticallyacceptable acid addition salts such as the hydrochloride is carried outin a conventional way by dissolving the base in a minimal amount ofethanol and adding ethanolic hydrogen chloride.

Adaptation of this procedure to2-[3-(p-toluenesulfonate)propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-oneobtained according to Example 12 with the requisite substitutedpiperazine (XVI) provides the Formula XI products indicated.

(a)2-[3-[4-(1,2-BENZISOTHIAZOL-3-YL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONE(XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR38## Crystallized from acetone,m.p. 105°-106° C.

Anal. Calcd. for C₂₆ H₃₂ N₆ O₂ S: C, 63.39; H, 6.55; N, 17.06; S, 6.51.Found: C, 63.19; H, 6.52; N, 16.90; S, 6.61.

NMR (CDCl₃): 1.32 (3,t, 7.2 Hz); 1.97 (2,m); 2.53 (2,q, 7.2 Hz); 2.65(6,m); 3.54 (4,m); 3.84 (2,t, 7.0 Hz); 4.10 (4,m); 6.89 (3,m); 7.26(4,m); 7.84 (2,m).

(b)2-[4-[3-[3-ETHYL-4,5-DIHYDRO-5-OXO-4-(2-PHENOXYETHYL)-1H-TRIAZOL-1-YL]PROPYL]-1-PIPERAZINYL]-3-PYRIDINECARBONITRILEHYDROCHLORIDE HYDRATE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR39##Crystallized from ethanol, m.p. 159°-161° C.

Anal. Calcd. for C₂₅ H₃₁ N₇ O₂.HCl.0.25H₂ O: C, 59.74; H, 6.53; N,19.51; Cl, 7.05. Found: C, 59.74; H, 6.44; N, 19.80; Cl, 7.09.

NMR (DMSO-d₆): 1.20 (3,t, 7.4 Hz); 2.14 (2,m); 2.67 (2,q, 7.4 Hz); 3.15(6,m); 3.64 (6,m); 4.15 (4,m); 6.95 (4,m); 7.29 (2,m); 8.17 (1,dd, 1.8Hz, 7.2 Hz); 8.50 (1,dd, 1.8 Hz, 4.8 Hz); 11.88 (1,bs).

(c)5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-2-[3-[4-(PHENYLMETHYL)-1-PIPERAZINYL]PROPYL]-3H-1,2,4-TRIAZOL-3-ONEDIHYDROCHLORIDE (XI, Y=Y, X₁ =0, n=2, R₂ =C₂ H₅, Z=--CH₂ C₆ H₅).Crystallized from ethanol, m.p. 214°-215° C.

Anal. Calcd. for C₂₆ H₃₅ N₅ O₂.2HCl: C, 59.77; H, 7.14; N, 13.40. Found:C, 59.82; H, 7.12; N, 13.25.

NMR (DMSO-d₆): 1.19 (3,t, 7.4 Hz); 2.10 (2,m); 2.65 (2,q, 7.4 Hz); 3.17(2,m); 3.52 (10,m); 3.95 (2,t, 5.0 Hz); 4.16 (2,t, 5.0 Hz); 4.40 (2s);6.94 (3,m); 7.46 (7,m).

(d)5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-2-[3-[4-(QUINOLIN-2-YL)-1-PIPERAZINYL]PROPYL]-3H-1,2,4-TRIAZOL-3-ONEDIHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR40## Crystallizedfrom ethanol, m.p. 208° C. (dec.).

Anal. Calcd. for C₂₈ H₃₄ N₆ O₂.2HCl: C, 60.10; H, 6.49; N, 15.02. Found:C, 60.02; H, 6.52; N, 14.96.

NMR (DMSO-d₆): 1.20 (3,t, 7.4 Hz); 2.19 (2,m); 2.66 (2,q, 7.4 Hz); 3.20(4,m); 3.75 (6,m); 3.98 (2,m); 4.18 (2,m); 4.97 (2,m); 6.93 (3,m); 7.30(2,m); 7.75 (4,m); 8.52 (2,m).

(e)2-[3-[4-(3-CHLORO-4-FLUOROPHENYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE HEMIHYDRATE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR41##Crystallized from ethanol, m.p. 171° C. (dec.).

Anal. Calcd. for C₂₅ H₃₁ ClFN₅ O₂.HCl.0.5H₂ O: C, 56.29; H, 6.24; N,13.13; H₂ O, 1.69. Found: C, 56.58; H, 6.22; N, 13.11; H₂ O, 1.61.

NMR (DMSO-d₆): 1.21 (3,t, 7.2 Hz); 2.18 (2,m); 2.68 (2,q, 7.2 Hz); 3.20(4,m); 3.45 (4,m); 3.74 (4,m); 3.98 (2,t, 5.0 Hz); 4.19 (2,t, 5.0 Hz);6.97 (4,m); 7.25 (9,m); 12.00 (1,bs).

(f)5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-2-[3-[4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL]PROPYL]-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR42## Crystallizedfrom ethanol, m.p. 169°-171° C.

Anal. Calcd. for C₂₆ H₃₂ F₃ N₅ O₂.HCl: C, 57.83; H, 6.16; N, 12.97.Found: H, 57.87; H, 6.20; N, 12.62.

NMR (DMSO-d₆): 1.21 (3,t, 7.4 Hz); 2.20 (2,m); 2.68 (2,q, 7.4 Hz); 3.24(8,m); 3.90 (6,m); 4.19 (2,t, 5.0 Hz); 6.97 (3,m); 7.28 (6,m); 11.75(1,bs).

(g)2-[3-[4-(2-CHLORO-6-PYRAZINYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR43## Crystallizedfrom ethanol, m.p. 194°-196° C.

Anal. Calcd. for C₂₃ H₃₀ ClN₇ O₂.HCl: C, 54.33; H, 6.15; N, 19.28.Found: C, 54.17; H, 6.17; N, 19.38.

NMR (DMSO-d₆): 1.20 (3,t, 7.2 Hz); 2.19 (2,m); 2.67 (2,q, 7.2 Hz); 3.11(4,m); 3.62 (6,m); 4.18 (6,m); 6.92 (3,m); 7.28 (2,m); 7.94 (1,s); 8.39(1,s); 11.90 (1,bs).

(h)2-[3-[4-(6-CHLORO-2-PYRIDINYL)-1-PIPERAZINYL]PROPYL]-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONEHYDROCHLORIDE (XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR44## Crystallizedfrom ethanol-ether, m.p. 191°-192° C.

Anal. Calcd. for C₂₄ H₃₁ ClN₆ O₂.HCl: C, 56.80; H, 6.36; N, 16.56.Found: C, 56.41; H, 6.39; N, 16.77.

NMR (DMSO-d₆): 1.20 (3,t, 7.5 Hz); 2.16 (2,m); 2.66 (2,q, 7.5 Hz); 3.10(4,m); 3.42 (4,m); 3.72 (2,m); 3.95 (3,m); 4.16 (3,m); 6.91 (5,m); 7.27(2,m); 7.61 (1,t, 8.0 Hz); 11.65 (1,bs).

(i) XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR45##

(j) XI, Y=H, X₁ =0, n=2, R₂ =C₂ H₅, ##STR46##

EXAMPLE 10 Preparation of Triazolones of Formula (XII) ##STR47##

The Formula (XII) triazolones wherein R₂ is lower alkyl can be preparedas follows: ##STR48##

An aqueous solution of the potassium salt of the phenol (1) is combinedwith an aqueous solution of the potassium salt of 3-chloropropionic acid(2). The resulting solution is heated at reflux for 10 min. and thencooled to 0° C. and concentrated hydrochloric acid added to pH 2. Theacidic solution is extracted with chloroform and the chloroform extractis treated with saturated aqueous sodium bicarbonate. The bicarbonatephase is acidified to pH 2 with concentrated hydrochloric acidprecipitating phenoxy acid (3). The phenoxy acid (3) is converted to theacid chloride by reaction with thionyl chloride (2 mol eq) in chloroformat reflux temperature. Excess thionyl chloride and chloroform areremoved under reduced pressure and the acid chloride used withoutfurther purification. Phenylalkanoyl chlorides are similarly preparedand both types are embodied in (4) wherein X₁ represents oxygen or adirect bond.

Acid chloride (4) is converted to the isocyanate by the procedure ofWashburne, et al., Synthetic Comm., 2, 227 (1972) employing toluene as asolvent. The reaction mixture is concentrated under reduced pressure andresidual isocyanate used without further purification. The isocyanate isdissolved in methylene chloride and added to a well stirred and cooled(0° C.) methylene chloride solution containing a hydrazide (6) toprovide the semicarbazide (7) which is purified by removing themethylene chloride under reduced pressure and flash chromatographingresidual oil.

Intramolecular cyclization of the semicarbazide (7) by treatment withaqueous potassium hydroxide (5 mol eq of 10% soln) and heating at 100°C. for a 5 hr. period affords the triazolone of Formula (XII) wherein R₂is lower alkyl.

The Formula (XII) triazolones wherein R₂ is hydrogen can be prepared byreacting the isocyanate (5) with tert.-butyl carbazate in methylenechloride at 0° C. to provide the tert.-butylcarboxy semicarbazide (8)which treated with a saturated HCl methanolic solution provides thesemicarbazide (9). Reaction of (9) with excess triethylorthoformate atreflux temperature affords the Formula (XII) triazolones wherein R₂ isH. ##STR49##

Adaptation of the foregoing procedures provides the following Formula(XII) triazolones.

(a) Y=2-CH₃ O, X₁ =0, n=2, R₂ =C₂ H₅.

Crystallized from methylene chloride, m.p. 141°-142° C.

Anal. Calcd. for C₁₃ H₁₇ N₃ O₃ : C, 59.30; H, 6.51; N, 15.96. Found: C,59.23; H, 6.55; N, 16.01.

(b) Y=H, X₁ =0, n=2, R₂ =tert.-butyl.

Crystallized from ethyl acetate-hexane.

Anal. Calcd. for C₁₄ H₁₉ N₃ O₂ : C, 64.35; H, 7.33; N, 16.08. Found: C,64.25; H, 7.40; N, 15.42.

(c) Y=4-CH₃ O, X₁ =0, n=2, R₂ =C₂ H₅.

Crystallized from acetone.

Anal. Calcd. for C₁₃ H₁₇ N₃ O₃ : C, 59.30; H, 6.51; N, 15.96. Found: C,59.51; H, 6.44; N, 15.16.

(d) Y=3-CF₃, X₁ =0, n=2, R₂ =C₂ H₅.

Crystallized from ethanol-water.

Anal. Calcd. for C₁₃ H₁₄ F₃ N₃ O₂ : C, 51.83; H, 4.68; N, 13.95. Found:C, 51.95; H, 4.65; N, 13.91.

(e) Y=3-Cl, X₁ =0, n=3, R₂ =C₂ H₅.

m.p. 120°-124° C.

(f) Y=3-Cl, X₁ =0, n=2, R₂ =C₂ H₅.

(g) Y=3-CF₃, X₁ =0, n=3, R₂ =C₂ H₅.

(h) Y=H, X₁ =direct bond, n=3, R₂ =C₂ H₅.

(i) Y=H, X₁ =direct bond, n=4, R₂ =C₂ H₅.

(j) Y=H, X₁ =0, n=2, R₂ =H.

Crystallized from ethanol-water.

Anal. Calcd. for C₁₀ H₁₁ N₃ O₂ : C, 58.52; H, 5.41; N, 20.48. Found: C,58.76; H, 5.36; N, 20.48.

(k) Y=3-Cl, X₁ =0, n=2, R₂ =H.

(l) Y=3-Cl, X₁ =0, n=3, R₂ =H.

(m) Y=3-CF₃, X₁ =0, n=3, R₂ =H.

EXAMPLE 11 Preparation of Piperazine Reactants

Appropriate piperazine reactants XIII and XVI employed in the process ofthe present invention are obtained in accordance with standard syntheticprocedures employed by those skilled in the art for preparation ofsimilar type compounds. C. B. Pollard, et al., J. Org. Chem., 24,764-767 (1959), Palazzo, et al., U.S. Pat. No. 3,381,009 and Wu, et al.,U.S. Pat. No. 3,717,634 all describe methods applicable for thepreparation of such compounds and the aforementioned patents areincorporated herein by reference. By application of these methods orother conventional methods, the following representative piperazinereactants are obtained.

(a) 3-(1-PIPERAZINYL)-1,2-BENZOISOTHIAZOLE ##STR50##

A mixture of 3-chloro-1,2-benzisothiazole (37.8 g., 0.235 mole) andpiperazine (304.2 g., 3.53 mole) is heated under an argon atmosphere fora period of 20 hr. at 120° C. in a closed reactor. The reaction mixtureis dissolved in 2 liters of water and the aqueous solution repeatedlyextracted with methylene chloride. Extracts are combined, dried overmagnesium sulfate and concentrated in vacuo. Residual material is takenup in ether, filtered and concentrated in vacuo to afford 24.4 g. (47%)of 3-(1-piperazinyl)-1,2-benzisothiazole free base as a viscous oil.

A sample of the free base converted to the hydrochloride salt in etherwith ethanolic hydrogen chloride and crystallized from methanol-ethanolaffords analytically pure 3-(1-piperazinyl)-1,2-benzisothiazolehydrochloride, m.p. 280° C. (dec.).

Anal. Calcd. for C₁₁ H₁₃ N₃ S.HCl: C, 51.66; H, 5.52; N, 16.43. Found:C, 51.34; H, 5.46; N, 16.16.

(b) N-(2-CHLORO-6-PYRAZINYL)PIPERAZINE ##STR51##

A mixture of 2,6-dichloropyrazine (5.0 g., 33.6 mmol),N-(ethoxycarbonyl)piperazine (5.57 g., 35.2 mmol) and potassiumcarbonate (13.9 g., 100.7 mmol) in acetonitrile is refluxed for a 24 hr.period. Insolubles are collected and the filtrate concentrated underreduced pressure. Crystallization of residual material from hexaneaffords N-(2-chloro-6-pyrazinyl)-1-ethoxycarbonylpiperazine.

Anal. Calcd. for C₁₁ H₁₅ ClN₄ O₂ : C, 48.80; H, 5.59; N, 20.70. Found:C, 48.62; H, 5.59; N, 20.70.

The carbethoxy protecting group is removed by treating the foregoingcompound with HCl to afford 4-(2chloro-6-pyrazinyl)piperazinehydrochloride.

Anal. Calcd. for C₈ H₁₁ ClN₄.HCl: C, 40.87: H, 5.14; N, 23.83. Found: C,41.05; H, 5.22; N, 23.68.

(c) N-(3-CHLORO-4-FLUOROPHENYL)PIPERAZINE ##STR52##

A xylene (20 ml.) solution of 3-chloro-4-fluoroaniline (5.0 g., 34.3mmol) and bis-(2-chloroethyl)amine hydrochloride (6.13 g., 34.3 mmol) isheated to reflux for 64 hrs. The mixture is extracted with warm waterand the aqueous phase then extracted with methylene chloride. Theaqueous phase is made basic with 50% sodium hydroxide and extracted withmethylene chloride which is dried over potassium carbonate andconcentrated under reduced pressure. Residual material is distilled andthe fraction having a b.p. of about 100° C. at 0.25 mmHg collected.Conversion of the amine to the hydrochloride salt and crystallizationfrom ethanol affords N-(3-chloro-4-fluorophenyl)piperazine.

Anal. Calcd. for C₁₀ H₁₂ ClFN₂ : C, 55.95; H, 5.63; N, 13.05. Found: C,56.26; H, 5.62; N, 12.99.

(d) N-(3-TRIFLUOROMETHYLPHENYL)PIPERAZINE ##STR53##

Reaction of 3-trifluoroaniline with bis-(2-chloroethyl)aminehydrochloride in xylene according to (c) above affords the title amine.

Anal. Calcd. for C₁₁ H₁₃ F₃ N₂ : C, 57.39; H, 5.69; N, 12.17. Found: C,56.62; H, 5.60; N, 11.69.

(e) N-(6-CHLORO-2-PYRIDINYL)PIPERAZINE ##STR54##

Reaction of 2,6-dichloropyridine with N-(ethoxycarbonyl)piperazineaccording to (b) above affords the title amine as the hydrochloride.

Anal. Calcd. for C₉ H₁₂ ClN₃.HCl: C, 46.17; H, 5.60; N, 17.95. Found: C,46.26; H, 5.64; N, 17.72.

(f) 2-CHLOROPYRIMYRIMIDIN-4-YLPIPERAZINE ##STR55##

Reaction of 2,6-dichloropyrimidine and piperazine according to (a) aboveand chromatographic purification affords the title amine.

(g) N(2-QUINOLINYL)PIPERAZINE ##STR56##

Reaction of piperazine with 2-chloroquinoline as set forth in (a) aboveprovides the title amine.

(h) 2-(PYRIMIDINYL)PIPERAZINE

EXAMPLE 12 Preparation of Triazolone Intermediates of Formulas XIV andXV

The product of Example 5"5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one" (5.0 g., 23.5mmol), chloropropanol (2.44 g., 25.8 mmol) and potassium carbonate (9.72g., 70.4 mmol) in 50 ml. of acetonitrile is heated to reflux for aperiod of 48 hr. with stirring. Water (50 ml.) is added and the mixtureextracted with methylene chloride which is dried over magnesium sulfateand concentrated under reduced pressure to afford2-(3-hydroxypropyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(XIV, Y=H, X₁ =0, n=2, R₂ =C₂ H₅). Purification is carried out by flashchromatography with ethyl acetate.

Anal. Calcd. for C₁₅ H₂₁ N₃ O₃ : C, 61.84; H, 7.26; N, 14.42. Found: C,61.61; H, 7.37; N, 14.19.

The alcohol is converted to the tosylate by dissolving in methylenechloride containing N,N-dimethyl-4-aminopyridine (0.05 mol eq) andtriethylamine (1.05 mol eq) and treating with tosyl chloride (1.1 moleeq) added in one portion at 0° C. with stirring. After standing forabout 24 hr. at 0° C., the mixture is treated with water and extractedseveral times with methylene chloride. The combined methylene chlorideextracts are dried over magnesium sulfate, filtered and concentratedunder reduced pressure. Flash chromatography of residual materialaffords2-[3-(p-toluenesulfonate)propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(XV, Y=H, X₁ =0, n=2, R₂ =C₂ H₅).

EXAMPLE 132-[3-[4-(3-Chlorophenyl)-1,2,3,6-tetrahydro-1-pyridinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one##STR57##

Reaction of2-[3-(p-toluenesulfonate)propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(XV, Y=H, X₁ =0, n=2, R₂ =C₂ H₅) with4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridine according to the procedureof Example 9 provides2-[3-[4-(3-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-onehydrochloride. Crystallized from ethanol, m.p. 163°-165° C.

Anal. Calcd. for C₂₆ H₃₁ ClN₄ O₂.HCl: C, 62.03; H, 6.41; N, 11.13.Found: C, 61.73; H, 6.39; N, 11.06.

NMR (DMSO-d₆): 1.21 (3,t, 7.4 Hz); 2.20 (2,m); 2.67 (2,q, 7.4 Hz); 2.80(2,m); 3.20 (4,m); 3.80 (6,m); 4.19 (2,t, 5.0 Hz); 6.22 (1,m); 6.95(3,m); 7.38 (6,m); 11.60 (1,bs).

EXAMPLE 145-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-4-ethyl-2,4-dihydro-2-(2-phenoxyethyl)-3H-1,2,4-triazol-3-oneHydrochloride ##STR58##

(a) Ethyl 4-[4-(3-Chlorophenyl)piperazin-1-yl]butyrate: Ethyl4-bromobutyrate (19.5 g, 0.10 mole); m-chlorophenylpiperazine (19.6 g.,0.10 mole); potassium carbonate (4.2 g., 0.04 mole); and a catalyticamount of potassium iodide were refluxed in 200 ml. acetonitrile forabout 28 hrs. The reaction mixture was cooled, filtered, andconcentrated to a crude oil which was partitioned between methylenechloride and water. The organic layer was washed two times with water,dried (MgSO₄), and concentrated in vacuo to about 30 g. of a light brownsolid. This material was purified using preparatory high pressure liquidchromatography. A silica gel column was used and was eluted using amixed solvent comprised of hexane-ethyl acetatemethylene chloride in aratio of 4.5:4.5:1. The eluent was concentrated to an oil, distilled(Kugelrohr) at approximately 160° at 0.4 Torr. to give 12.6 g. (41%) ofyellow oil. This crude ester product was used without furtherpurification.

(b) 4-(3-Chlorophenyl)piperazin-1-ylbutanoic Acid Hydrazide: Crude ethyl4-[4-(3-chlorophenyl)piperazin-1-yl]butyrate (prepared above in (a), 9.9g., 0.03 mole) in 20 ml. ethanol was added under a nitrogen atmosphereto a cold stirred solution of anhydrous hydrazine (1.1 g., 0.035 mole)in 5 ml. absolute ethanol. When addition was completed, the reaction wasrefluxed for 7 days using IR to monitor reaction progress whileobserving disappearance of the C═O stretching frequency at 1730 cm⁻¹. Areaction oil, obtained by concentration in vacuo was partitioned betweenether and water. The water layer was extracted three times withadditional ether; the ether portions all combined and dried (MgSO₄) andconcentrated in vacuo to approximately 10 g. of the crude hydrazideproduct which was used without further purification.

(c) A portion of the hydrazide (prepared above in (b), 4.9 g., 0.016mole) in 50 mL methylene chloride was added to a cold solution of ethylisocyanate (1.2 g., 0.016 mole) in 50 ml methylene chloride. The coldreaction solution was stirred for 1 hr. and then concentrated in vacuoaffording a theoretical yield of the crude ethyl semicarbazate which wascombined with 4.6 g. KOH in 100 ml. water and refluxed for approximately5 hrs. The reaction mixture was then cooled and the pH adjusted to 8using 6N HCl. This solution was extracted three times with ether, theether portions combined and dried (K₂ CO₃) and concentrated in vacuo toyield 4 g. (72%) of the crude 1,2,4-triazol-3-one as a white solid.

This triazolone intermediate product was combined with1-bromo-2-phenoxyethane (2.5 g., 0.01 mole); potassium carbonate (4.6g., 0.03 mole) and a catalytic amount of potassium iodide in 150 ml.acetonitrile. This reaction mixture was refluxed for approximately threedays during which time small amounts of the phase transfer catalysttetrabutylammonium hydrogen sulfate (TBAHS, 0.035 g., 0.1 mole) and anadditional equivalent of K₂ CO₃ were added. At this point monitoring ofthe reaction by TLC indicated its completeness. The reaction mixture wascooled, filtered, and concentrated to an oil which was partitionedbetween methylene chloride and water. The water layer was extractedtwice with additional methylene chloride, the methylene chlorideportions combined and dried (MgSO₄) and concentrated to approximately 5g. of crude material. This crude material was purified by flashchromatography utilizing a silica column and eluting with methanol(4%)-methylene chloride (96%). Concentration in vacuo gave a yellow oilwhich was converted to the hydrochloride salt by treatment withethanolic HCl. Recrystallization from ethanol gave 2.7 g. (49%) whitesolid, m.p. 153°-155°.

Anal. Cacld. for C₂₅ H₃₂ ClN₅ O₂.HCl: C, 59.29; H, 6.57; N, 13.83.Found: C, 59.40; H, 6.55; N, 13.92.

NMR (DMSO-d₆): 1.16 (3,t, 7.0 Hz); 2.15 (2,m); 2.70 (2,t, 6.8 Hz); 3.20(4,m); 3.58 (8,m); 4.00 (2,t, 5.0 Hz); 4.25 (2,t, 5.0 Hz); 6.91 (6,m);7.27 (3,m); 11.60 (1,bs).

EXAMPLE 155-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one##STR59##

(a) 2-Phenoxyethyl isocyanate:

3-Phenoxypropionic acid (3.0 g., 0.02 mole) was dissolved in 10 ml. ofmethylene chloride containing a catalytic amount of dimethylformamide.Thionyl chloride (2.7 ml., 0.04 mole) was added under a nitrogenatmosphere in a single portion at ambiant temperature. After beingallowed to stand and react for 2 hrs., the reaction mixture wasconcentrated in vacuo to yield 3.3 g. (100%) of the crude acid chlorideproduct.

The crude acid chloride (3.3 g., 0.02 mole) was dissolved in 2 ml.toluene and heated to 100° whereupon azidotrimethlysilane (2.1 g., 2.4ml., 0.02 mole) in 2 ml. of toluene was added dropwise at such a ratethat nitrogen evolution remained controlled. The reaction was monitoredby IR for disappearance of the C═O stretching mode at 1800 cm⁻¹ and wascomplete after about 4-6 hrs. The solvent and excess reagent weredistilled under reduced pressure affording the brown-orange isocyanatewhich was used without further purification in the next step.

Note: While 3-phenoxypropionic acid is commercially available, it canalso be conveniently prepared by alkylation of phenol with ethyl3-bromopropionate followed by ester hydrolysis to give the desiredintermediate, 3-phenoxypropionic acid.

(b) 4-(3-Chlorophenyl)-1-piperazinebutanoic AcidPhenoxyethylsemicarbazide:

4-(3-Chlorophenyl)-1-piperazinebutanoic acid hydrazide (prepared abovein Example 14, 4.5 g., 0.015 mole) in 100 ml. methylene chloride at 0°was treated with the crude phenoxyethyl isocyanate prepared above in(a). After being stirred at 0° for about 15 min., the reaction mixturewas allowed to warm to room temperature and stand overnight.Concentration in vacuo and drying gave 7.6 g. of brown solid product.This crude solid was purified by flash chromatography through a silicacolumn eluting with 15% methanol-methylene chloride to yield 5 g. (61%)semicarbazide product.

(c) The semicarbazide intermediate (prepared above in (b), 5.0 g., 0.01mole) was refluxed overnight in 60 ml. of 5% KOH solution. Followingreaction, this mixture was cooled, neutralized (pH 7) with 6N HCl.Thorough extraction with methylene chloride-ether followed by drying(MgSO₄) and concentration of the extracts gave 4.4 g. (91%) of crude1,2,4-triazol-3-one product. Recrystallization from ethanol gives thepure product as white crystals, m.p. 159°-161°.

Anal. Calcd. for C₂₃ H₂₈ ClN₅ O₂ : C, 62.51; H, 6.39; N, 15.85. Found:C, 62.35; H, 6.34; N, 15.57.

NMR (DMSO-d₆): 1.83 (2,m); 2.50 (8,m); 3.11 (4,m); 3.92 (2,t, 5.0 Hz);4.15 (2,t, 5.0 Hz); 6.90 (6,m); 7.20 (3,m); 11.38 (1,s).

EXAMPLE 165-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-2-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-oneHydrochloride Hydrate ##STR60##

5-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one(prepared above in Example 15, 3.9 g., 0.01 mole); ethyl bromide (1.1g., 0.75 ml., 0.01 mole); potassium carbonate (3.7 g., 0.03 mole) and acatalytic amount of potassium iodide were dissolved in 250 ml.acetonitrile and refluxed for several days. The reaction was monitoredusing thin layer chromatography (TLC) to observe the disappearance ofthe starting triazolone. An additional 0.5 equivalent of the ethylbromide was added and refluxing continued for a total of five days. Atthis point, no starting triazolone was observed by TLC. The reactionmixture was cooled, filtered, concentrated in vacuo and partitionedbetween methylene chloride and water. The water layer was extracted withmethylene chloride, the methylene chloride portions combined and dried(MgSO₄) and concentrated to 4.1 g. yellow oil. This oil was purified byflash chromatography through a silica gel column eluting with 6%methanol-methylene chloride. Concentration of the eluent yielded 2.8 g.orange oil which was converted to the hydrochloride salt by treatmentwith ethanolic HCl to afford 1.9 g. white solid, m.p. 150°-153°.

Anal. Calcd. for C₂₅ H₃₂ ClN₅ O₂.HCl.1/3H₂ O: C, 58.59; H, 6.62; N,13.67. Found: C, 58.68; H, 6.59; N, 13.36.

NMR (DMSO-d₆): 1.20 (3,t, 7.0 Hz); 2.18 (2,m): 2.78 (2,t, 6.8 Hz); 3.30(8,m); 3.70 (4,m); 3.96 (2,t, 5.0 Hz); 4.17 (2,t, 5.0 Hz); 7.00 (6,m);7.28 (3,m); 11.05 (1,bs).

What is claimed is:
 1. A compound of Formula XI ##STR61## wherein n is2-4;R₂ is hydrogen or lower alkyl; X₁ is oxygen or a direct bond; Y ishydrogen, halogen, lower alkoxy or CF₃ with the proviso that when Y ishydrogen, n cannot be 2, R₂ cannot be ethyl, X₁ cannot be oxygen and Zcannot be phenyl having a mono halogen substituent; Z is benzyl or aradical selected from the group ##STR62## wherein R₃ is hydrogen orhalogen; R₄ is halogen or CF₃ ; R₅ is hydrogen, halogen or cyano; R₆ ishydrogen or halogen;or a pharmaceutically acceptable acid addition saltthereof.
 2. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(3-phenoxypropyl)-3H-1,2,4-triazol-3-one.3. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(4-phenoxybutyl)-3H-1,2,4-triazol-3-one.4. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-[2-(2-methoxyphenoxy)ethyl]-3H-1,2,4-triazol-3-one.5. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-(1,1-dimethylethyl)-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.6. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-[2-(4-methoxyphenoxy)ethyl]-3H-1,2,4-triazol-3-one.7. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-[2-[3-trifluoromethyl)phenoxy]ethyl]-3H-1,2,4-triazol-3-one.8. The compound of claim 1 which is4-[3-(3-chlorophenoxy)propyl]-2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-3H-triazol-3-one.9. The compound of claim 1 which is4-[2-(3-chlorophenoxy)ethyl]-2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.10. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-[3-[3-(trifluoromethyl)phenoxy]propyl]-3H-1,2,4-triazol-3-one.11. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(3-phenylpropyl)-3H-1,2,4-triazol-3-one.12. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(4-phenylbutyl)-3H-1,2,4-triazol-3-one.13. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.14. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-4-[2-(3-chlorophenoxy)ethyl]-3H-1,2,4-triazol-3-one.15. The compound of claim 1 which is4-[3-(3-chlorophenoxy)propyl]-2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-3H-1,2,4-triazol-3-one.16. The compound of claim 1 which is2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-4-[3-[3-(trifluoromethyl)phenoxy]propyl]-3H-1,2,4-triazol-3-one.17. The compound of claim 1 which is2-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.18. The compound of claim 1 which is2-[4-[3-[3-ethyl-4,5-dihydro-5-oxo-4-(2-phenoxyethyl)-1H-triazol-1-yl]propyl]-1-piperazinyl]-3-pyridinecarbonitrile.19. The compound of claim 1 which is5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-2-[3-[4-(phenylmethyl)-1-piperazinyl]propyl]-3H-1,2,4-triazol-3-one.20. The compound of claim 1 which is5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-2-[3-[4-(quinolin-2-yl)-1-piperazinyl]propyl]-3H-1,2,4-triazol-3-one.21. The compound of claim 1 which is2-[3-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.22. The compound of claim 1 which is5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-2-[3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]propyl]-3H-1,2,4-triazol-3-one.23. The compound of claim 1 which is2-[3-[4-(2-chloro-6-pyrazinyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-1-one.24. The compound of claim 1 which is2-[3-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.25. The method for treating a mammal afflicted with depressioncomprising administering to said mammal a therapeutically effectiveantidepressant amount of a compound of claim 1 or a pharmaceuticallyacceptable acid addition salt thereof.
 26. The pharmaceuticalcomposition comprising an antidepressant amount of a compound of claim 1or a pharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier. 27.5-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-4-ethyl-2,4-dihydro-2-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.28.5-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.29.5-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-2-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.